Conjugation—Deconjugation Reactions in Drug Metabolism and Toxicity

Section I: Transferases and Hydrolases Involved in Phase II Conjugation—Deconjugation Reactions, Genetic Polymorphism and Regulation of Expression.- 1 The Uridine Diphosphate Glueuronosyltransferase Multigene Family: Function and Regulation With 7 Figures.- A. Introduction.- B. The Physiological Roles of Uridine Diphosphate Glucuronosyltransferases.- I. Endogenous Compound Metabolism.- II. Drug and Xenobiotic Conjugation.- III. Role of Glucuronidation in Olfaction and Glycolipid Biosynthesis.- C. Localisation of Uridine Diphosphate Glucuronosyltransferases.- I. Tissue Distribution.- II. Topology of Uridine Diphosphate Glucuronosyltransferases in the Endoplasmic Reticulum.- D. The Uridine Diphosphate Glueuronosyltransferase Multigene Family.- I. Elucidation of Uridine Diphosphate Glueuronosyltransferase Heterogeneity.- II. Primary Structure and Post-Translational Processing of Uridine Diphosphate Glucuronosyltransferases.- III. Substrate Specificity of Uridine Diphosphate Glueuronosyltransferase Isoforms.- 1. Rat Uridine Diphosphate Glueuronosyltransferase Isoforms.- 2. Human Uridine Diphosphate Glueuronosyltransferase Isoforms.- IV. Structure and Mapping of Uridine Diphosphate Glueuronosyltransferase Gene Loci.- E. Factors Affecting Uridine Diphosphate Glucuronosyltransferase Expression.- I. Ontogeny.- II. Induction by Xenobiotics.- III. Genetic Deficiencies.- 1. Deficiency of Androsterone Uridine Diphosphate Glueuronosyltransferase.- 2. The Gunn Rat.- 3. Crigler-Najjar Syndrome.- 4. Gilbert Syndrome.- F. Concluding Remarks.- References.- 2 Sulfotransferase Enzymes With 6 Figures.- A. Introduction.- B. Classification of Sulfotransferase Enzymes.- I. Introduction.- II. Human Sulfotransferase Enzyme Classification.- III. Rat Sulfotransferase Enzyme Classification.- IV. Molecular Classification of Sulfotransferase Enzymes.- C. Assays for Sulfotransferase Enzymes.- D. Purification of Sulfotransferase Enzymes.- E. Molecular Cloning of Sulfotransferase Enzyme cDNAs.- I. Introduction.- II. Phenol Sulfotransferase cDNAs.- III. Estrogen Sulfotransferase cDNAs.- IV. Hydroxysteroid Sulfotransferase cDNAs.- V. Flavonol Sulfotransferase cDNAs.- VI. Conclusions.- F. Properties of Sulfotransferase Enzymes.- I. Introduction.- II. Phenol Sulfotransferase Properties.- 1. Human Phenol Sulfotransferase Properties.- 2. Rat Phenol Sulfotransferase Properties.- 3. Properties of Phenol Sulfotransferase in Other Species.- III. Estrogen Sulfotransferase Properties.- IV. Hydroxysteroid Sulfotransferase Properties.- V. Flavonol Sulfotransferase Properties.- G. Regulation of Sulfotransferase Enzymes.- I. Introduction.- II. Sulfotransferase Enzyme Pharmacogenetics.- III. Humoral Regulation of Sulfotransferase Enzymes.- H. Conclusion.- References.- 3 Regulation of Expression of Rat Liver Glutathione S-Transferases: Xenobiotic and Antioxidant Induction of the Ya Subunit Gene With 6 Figures.- A. Perspectives.- B. Occurrence and Structure.- C. Nomenclature.- D. cDNA and Genomic Clones of Rat Glutathione S-Transferases.- I. cDNA Clones of the Alpha Gene Family (Subunits Yal, Ya2, and Yc).- II. cDNA Clones of the Mu Gene Family (Subunits Ybl, Yb2, Yb3, and Yb4).- III. cDNA Clones of the Pi Gene Family (Subunit Yp).- IV. cDNA Clones of the Theta Gene Family (Subunit Yrs).- V. cDNA Clones of the Microsomal Gene Family.- E. Structure of Glutathione S-Transferase Genes.- I. Glutathione S-Transferase Alpha Class Family.- II. Glutathione S-Transferase Mu Class Family.- III. Glutathione S-Transferase Pi Class Family.- F. Structure—Function Analysis of Glutathione S-Transferases.- I. Site-Directed Mutagenesis.- II. Crystallographic Solution of Glutathione S-Transferases.- G. Transcriptional Regulation of Glutathione S-Transferase Gene Expression.- I. Pi Gene (Subunit Yp).- II. Alpha Gene (Subunit Ya1).- 1. Identification of Regulatory Elements.- 2. Sequence Requirements of the Antioxidant-Responsive Element for Basal and Xenobiotically Inducible Activity.- 3. Induction of the Ya Subunit Gene by Phenolic Antioxidants Through the Antioxidant-Responsive Element.- 4. DNA Binding Studies.- H. Transcriptional Activation Through the Antioxidant and Xenobiotic-Responsive Element: A Study of Model Compounds.- I. Mechanisms of Induction of Glutathione S-Transferase Ya1 Subunit Gene.- References.- 4 Human N-Acetyltransferases With 3 Figures.- A. Introduction.- B. Biochemical and Immunochemical Studies on Liver Cytosolic N-Acetyltransferases.- C. Molecular Genetics of N-Acetyltransferases.- I. Identification of N-Acetyltransferase Genes.- 1. Cloning and Chromosomal Mapping.- 2. Heterologous Expression.- II. Properties of Hepatic and Recombinant N-Acetyltransferases.- 1. Substrate Selectivity.- 2. Stability.- D. The NAT 2 Locus.- I. Structural Heterogeneity.- 1. Coding Region Mutations.- 2. Far Downstream Mutations.- 3. Allelic and Genotypic Frequencies.- II. Characterization of Mutants.- 1. mRNA and Protein Content in Genotypically Defined Liver Tissue.- 2. Transfection of Mammalian Cells with NAT 2 Alleles and Chimeric Gene Constructs.- E. The NAT1 Locus.- I. Structural Heterogeneity.- 1. Allelic Variants of Caucasian NAT1.- 2. Ethnic Differences in Wild-Type NAT1.- II. Functional Aspects of Allelic Heterogeneity.- 1. Individual Variation in N-Acetylation of NAT1 Substrates In Vivo.- 2. Individual Variation in N-Acetylation of NAT1 Substrates In Vitro.- F. Independent Expression of NAT1 and NAT2.- References.- 5 Genetic Regulation of the Subcellular Localization and Expression of Glucuronidase With 5 Figures.- A. Introduction.- B. Endoplasmic Reticulum Glucuronidase.- I. Background.- II. Species Distribution of Liver Endoplasmic Reticulum Glucuronidase.- III. Organ and Cellular Distribution of the Endoplasmic Reticulum Glucuronidase—Egasyn Complex.- IV. Subcellular Distribution of the Complex.- 1. Background.- 2. Glucuronidase is Located Within the Lumen of the Endoplasmic Reticulum.- V. Lysosomal Glucuronidase was Associated with Egasyn During Subcellular Transit.- VI. Egasyn is an Esterase.- 1. Background.- 2. Identity of Egasyn Esterase.- VII. The Egasyn—Glucuronidase Interaction is Highly Specific.- VIII. The Esterase—Active Site of Egasyn is Involved in Complex Formation.- IX. The Propeptide Portion of the Glucuronidase Precursor is Involved in Complex Formation.- X. Sequence Similarity of the Glucuronidase Propeptide with Portions of the Reactive Site Region of the Serpin Superfamily.- XI. Endoplasmic Reticulum Retention Signal of Egasyn.- XII. Endoplasmic Reticulum Retention Signals of Other Esterases.- XIII. Is Complexation with Other Proteins a General Function of Endoplasmic Reticulum Esterases?.- XIV. Physiological Role of Endoplasmic Reticulum Glucuronidase.- XV. Physiological Role of Endoplasmic Reticulum Esterases.- XVI. Abnormal Subcellular Distribution of Glucuronidase in the Gusn Mouse.- C. Regulation of Expression of Glucuronidase.- I. Androgen-Regulated Genetic Elements.- II. Estrogen-Specific (Gus-e) Genetic Elements.- III. Tissue-Specific (Gus-u) and Temporal (Gus-t) Genetic Elements.- D. An Exoglucuronidase Acting on Nonsulfated Glycosaminoglycans.- E. Inherited ?-Glucuronidase Deficiency States.- I. Mucopolysaccharidosis VII in Humans.- II. Animal Models of Mucopolysaccharidosis VII.- References.- 6 Microsomal Amidases and Carboxylesterases With 5 Figures.- A. Introduction.- B. Distribution of Microsomal Amidases/Carboxylesterases.- C. Purification of Microsomal Amidases/Carboxylesterases from Different Species.- I. Rabbit.- II. Rat.- III. Mouse.- IV. Hamster.- V. Guinea pig.- VI. Dog.- VII. Human.- VIII. Monkey.- IX. Pig.- X. Cow.- D. Physical and Chemical Characteristics of Amidases/Carboxylesterases.- I. Amino Acid Compositions and Amino Acid Sequences.- II. Glycosylation Sites.- III. Active Sites.- IV. Antigenicities.- E. Catalytic Properties.- I. Catalytic Activities.- II. Reaction Mechanisms.- III. Enzyme Inhibition.- 1. Substrate Inhibition.- 2. Inactivation of Active Sites.- F. Regulation of Expression of Amidases/Carboxylesterases.- I. Regulation by Amidase/Carboxylesterase Genes.- II. Regulation by Hormones.- 1. Regulation by Sex Hormones.- 2. Regulation by Pituitary Hormones.- 3. Regulation by Pancreatic Hormones.- III. Enzyme Induction.- G. Role of Amidase/Carboxylesterase in Arylacetamide Toxicities and Carcinogenicities.- I. Toxicity of Phenacetin and Acetaminophen.- II. Carcinogenicity of Arylamines.- References.- 7 O-, N, and S-Methyltransferases With 2 Figures.- A. Introduction.- B. The Methyl Transfer Reaction.- C. S-Adenosyl-L-Methionine.- D. O-Methylation.- I. Overview.- II. Catechol O-Methyltransferase.- 1. Enzymology.- 2. Inhibitors.- 3. Role of Catechol O-Methyltransferase in the Therapy of Parkinson’s Disease.- 4. Molecular and Structural Biology.- III. Hydroxyindole O-Methyltransferase.- 1. Enzymology.- 2. Molecular and Structural Biology.- E. N-Methylation.- I. Overview.- II. Phenethanolamine N-Methyltransferase.- 1. Enzymology.- 2. Molecular and Structural Biology.- III. Histamine N-Methyltransferase.- 1. Enzymology.- 2. Molecular and Structural Biology.- F. S-Methylation.- I. Overview.- II. S-Methyltransferases.- G. Pharmacogenetics of Methyltransferases.- H. Conclusion.- References.- Section II: Regulation of Phase II Conjugation: Deconjugation Reactions in Intact Cells and Tissues.- 8 Cofactor Supply as a Rate-Limiting Determinant of Hepatic Conjugation Reactions With 5 Figures.- A. Introduction.- I. Energy Requirements for Conjugation.- II. Metabolic Burden of Conjugation.- III. Drug Substrate Concentration as a Rate-Determining Factor for Conjugation Reactions.- B. Models Used to Study Regulation of Conjugation.- C. Glucuronidation.- I. Uridine Diphosphate Glucuronic Acid Metabolism.- II. Carbohydrate Supplies.- 1. Glycogen Levels.- 2. Endocrine Disorders and Glucuronidation.- III. Cellular Energetics and Glucuronidation.- 1. Hypoxia.- 2. Metabolic Inhibitors.- IV. The Cellular Oxidation—Reduction State and Glucuronidation.- V. Other Factors Influencing Glucuronidation.- 1. Volatile Anesthetics.- 2. Effects of Drugs and Other Chemicals.- VI. Intracellular Transport of Uridine Diphosphate Glucuronic Acid.- D. Sulfate Conjugation.- I. 3’-Phosphoadenosine-5’-Phosphosulfate Metabolism.- II. Availability of Inorganic Sulfate and Rates of Hepatic Sulfation.- III. Rate-Limiting Factors for Sulfate Conjugation.- IV. Cellular Energetics and Sulfation.- V. Other Metabolic Factors Affecting 3’-Phosphoadenosine-5’-Phosphosulfate Levels.- VI. Futile Cycling of Sulfate Conjugates.- E. Glutathione.- I. Glutathione Synthesis and Metabolism.- II. Mechanisms of Depletion of Hepatic Glutathione.- 1. Conjugation of Electrophilic Compounds.- 2. Oxidative Stress.- 3. Inhibition of Glutathione Synthesis.- 4. Fasting and Nutritional Influences.- 5. Hepatic Energetics.- 6. Other Factors Which Decrease Glutathione.- III. Methods of Increasing Hepatic Concentrations of Glutathione.- F. Other Pathways of Hepatic Conjugation.- References.- 9 Regulation of Drug Conjugate Production by Futile Cycling in Intact Cells With 4 Figures.- A. Introduction.- B. Properties of Hydrolases and Transferases Related to Futile Cycling of Conjugates.- C. Futile Cycling of Glucuronide Conjugates.- D. Futile Cycling of Sulfate Conjugates.- E. Conclusion.- References.- 10 Pharmacokinetic Modeling of Drug Conjugates With 22 Figures.- A. Introduction.- B. Hepatic Modeling: Tubular Flow Model.- I. Transmembrane Barrier.- II. Zonation of Enzymic Activities.- III. Nonlinear Protein Binding.- IV. Futile Cycling.- V. Flow.- VI. Cosubstrate.- C. Concluding Remarks.- References.- 11 Regulation of Drug Conjugate Processing by Hepatocellular Transport Systems With 1 Figure.- A. Introduction.- B. Transport Across the Basolateral Domain.- I. Transport from Plasma into the Hepatocyte.- 1. Na+-Taurocholate Cotransport — A Multispecific System.- 2. Na+-Independent Transport Systems.- II. Transport from Hepatocyte to Plasma.- C. Transport Across the Canalicular Domain.- I. Transport Systems from the Hepatocyte into Bile.- 1. P-Glycoprotein.- 2. Bile Acid Transport Systems.- 3. Nonbile Acid Organic Anion Transport Systems.- II. Transport from Bile into the Hepatocyte.- References.- Section III: Pharmacology and Toxicology of Drug Conjugates.- 12 Biologically Active Conjugates of Drugs and Toxic Chemicals With 5 Figures.- A. Introduction.- B. Biologically Active Drug Conjugates.- I. Morphine-6-Glucuronide.- II. Minoxidil Sulfate.- III. Other Drug Conjugates.- 1. Retinoid Glucuronides.- 2. Fatty Acid Conjugates.- 3. Acyl-Linked Glucuronides.- 4. Bile Acid Conjugates.- 5. Polymeric Conjugates.- C. Steroids.- I. Glucuronides.- II. Sulfates.- 1. Pregnenolone Sulfate.- 2. Dehydroepiandrosterone Sulfate.- D. Toxic Conjugates Formed and Released from Liver.- I. Poly cyclic Aromatic Hydrocarbons.- II. Glutathione Conjugates.- E. Activation of Drug Conjugates by Targeted Enzymes.- F. Conclusions.- References.- 13 Acyl Glucuronides as Chemically Reactive Intermediates With 10 Figures.- A. Acyl Glucuronides as Chemically Reactive Intermediates.- B. Intramolecular Rearrangements.- C. Nucleophilic Displacement.- D. Covalent Bonding to Biopolymers.- I. Albumin as Nucleophile.- II. Four Reagents and Three Mechanisms.- III. Product Stabilities.- E. Implications.- References.- 14 Roles of Uridine Diphosphate Glucuronosyltransferases in Chemical Carcinogenesis With 9 Figures.- A. Introduction.- I. Control of Nucleophilic Metabolites by Glucuronidation Preventing their Conversion to Electrophilic, Reactive Metabolites.- II. Initiation of Carcinogenesis by Reactive Metabolites.- III. Tumor Promotion and Reactive Metabolites.- B. Glucuronides as Transport Forms of Carcinogens.- I. Bladder Carcinogenesis.- II. Colon Carcinogenesis.- C. Role of Glucuronidation in Detoxication of Carcinogens.- I. Aromatic Hydrocarbons.- 1. Benzo(a)pyrene.- 2. Benzene.- 3. 2-Hydroxybiphenyl.- II. Aromatic Amines.- 1. 2-Acetylaminofluorene.- 2. Others.- D. Metabolism of Carcinogens by Isozymes of the Uridine Diphosphate Glucuronosyltransferase Enzyme Superfamily.- I. Factors Controlling Glucuronide Formation in the Intact Cell.- 1. The Uridine Diphosphate Glucuronic Acid Level.- 2. Localization of Uridine Diphosphate Glucuronosyltransferase: Latency.- 3. Interaction of Uridine Diphosphate Glucuronosyltransferases with Phospholipids.- 4. Sequestration of Substrates in the Microsomal Membrane.- II. Functions of Uridine Diphosphate Glucuronosyltransferase Isozymes.- 1. Uridine Diphosphate Glucuronosyltransferase Enzyme Superfamily.- 2. Substrate Specificity of Phenol Uridine Diphosphate Glucuronosyltransferases in Family 1A.- E. Regulation of Uridine Diphosphate Glucuronosyltransferase Isozymes.- I. General Features.- II. Regulation of Phenol Uridine Diphosphate Glucuronosyltransferase by the Ah Receptor.- III. Persistent Alterations of Phenol Uridine Diphosphate Glucuronosyltransferase in Preneoplastic Liver.- F. Conclusions.- References.- 15 Sulfonation in Chemical Carcinogenesis With 11 Figures.- A. Introduction.- B. Metabolic Activation of Chemical Carcinogens by Sulfonation.- I. Aromatic Amides and Amines.- 1. 2-Acetylaminofluorene.- 2. 4-Acetylaminobiphenyl.- 3. 4-Acetylaminostilbene.- 4. 2-Acetylaminophenanthrene.- 5. Phenacetin.- 6. 4-Aminoazobenzene, N-Methyl-4-Aminoazobenzene, and N,N- Dimethyl-4-Aminoazobenzene.- 7. Benzidine.- 8. Heterocyclic Aromatic Amines.- 9. Hydroxylamine-0-Sulfonic Acid.- II. Alkenylbenzenes.- 1. Safrole and Estragóle.- 2. 1’-Hydroxy-2’,3’-Dehyroestragole.- III. Polynuclear Aromatic Hydrocarbons.- 1. Methyl-Substituted Aromatic Hydrocarbons.- 2. Cyclopenta-Fused Aromatic Hydrocarbons.- 3. Phenols, Bay-Region Dihydrodiols, Tetraols of Polynuclear Aromatic Hydrocarbons.- IV. Nitrotoluenes.- V. ?-Hydroxynitrosamines.- VI. Miscellaneous Compounds.- 1. 3-Hydroxypurines.- 2. ?-Aminoalcohols.- 3. Hycanthone.- 4. Quercetin.- 5. 5-Hydroxymethylfurfural.- C. Concluding Remarks.- References.- 16 Glutathione Conjugate-Mediated Toxicities With 8 Figures.- A. Introduction.- B. Glutathione-Dependent Activation of Halogenated Alkanes and Alkenes.- I. Glutathione-Dependent Mutagenicity.- II. Cysteine Conjugate ?-Lyase-Dependent Mutagenicity.- III. Glutathione-Dependent Nephrotoxicity.- 1. The Role of Renal Transport.- 2. The Role of Renal Bioactivation.- 3. Mechanisms of Toxicity.- 4. The Role and Regulation of ?-Lyase.- C. Glutathione- and Quinone-Mediated Toxicities.- I. Biological (Re)activity of Quinone-Thioethers.- II. Enzyme Inhibition by Quinone-Thioethers.- III. Free Radical Formation by Quinone-Thioethers.- IV. Quinone-Thioether-Catalyzed Methemoglobinemia.- V. Quinone-Thioethers and Nephrotoxicity.- VI. Quinone-Thioethers and Neurotoxicity.- VII. Quinone-Thioethers and Alcoholism?.- VIII. ?-Glutamyl Transpeptidase and Quinone-Thioether-Mediated Toxicities.- D. Reversible Glutathione Conjugations and Their Toxicological Significance.- I. Isothiocyanates.- II. ?, ?-Unsaturated Aldehydes (Acrolein).- III. Isocyanates.- E. Pharmacologically Active Glutathione Conjugates.- I. Leukotrienes.- II. Nitric Oxide and Endothelium-Derived Relaxing Factor.- F. Summary.- References.- 17 Challenges and Directions for Future Research.- A. Introduction.- B. Search for Factors Regulating Polymorphic Expression of Phase II Conjugating and Deconjugating Enzymes.- I. Genetic Factors.- II. Environmental Factors.- C. Net Conjugate Production by Intact Cells.- I. Interaction Between Transferases and Hydrolases.- II. Cofactor Supply.- III. Transport of Conjugated Metabolites.- D. Mechanisms of Biologically Active Conjugates.- I. Chemically Active Toxic Conjugates.- 1. Sulfonates.- 2. Acyl Glucuronides.- 3. Glutathione Conjugates.- II. Pharmacologically Active Conjugates.- 1. Direct Acting Conjugates.- 2. Carrier Conjugates.- E. Conclusion.- References.